The purpose of this continuation application is to further study two neuropathologic markers of Parkinson's disease (PD), neuronal loss in the substantia niqra (SN) and diminished striatal dopamine levels, in brains of Japanese-American male decedents who were participants in the population based Honolulu Heart Program/Honolulu-Asia Aging Study. These are used as continuous endpoints to identify risk factors utilizing exposure data accumulated prospectively over the past 39 years. Findings include significantly lower SN neuron densities in PD cases compared to controls without PD. Further, duration of PD is highly correlated with SN neuron density. Brains with incidental Lewy bodies have intermediate mean densities. These relationships are strongest for the ventrolateral quadrant. Mid-life risk factors found preliminarily to predict low SN neuron density at death include high total kilocalorie intake, dietary iron and manganese, non-smoking of cigarettes, work on a sugar or pineapple plantation, high body mass index, increased time spent in edentary activity, and (in late life) slowed reaction time. Contrary to expectation, an association of advanced age with deceased SN neuron density was not found. To assess the influence of age with qreater certainty a new Aim is proposed: measurement of SN neuron densities in study subjects dying at a younger age, using archived materials from 160 cohort autopsies done prior to 1991. A second important and unexpected finding is of remarkably low SN neuron densities in the absence of Lewy bodies, but in association with parkinsonian signs, in a subset of the decedents. A second new Aim is proposed to extend investigations of this subset by applying a-synuclein immunohistochemistry to areas of brainstem, limbic regions, cortex, and olfactory bulb. These histopathologic studies will help to determine if the subset of decedents with isolated SN neuron loss represents a prodromal phase of PD, or a pathogenesis not associated with a-synucleinopathy. Continuation will allow accrual of SN neuron density measurements for 800 total autopsies, and 440 striatal dopamine assays. The greater numbers will dramatically enhance statistical power for substantiating risk factors preliminarily identified or suspected. This will also provide opportunity to examine the influence of a wider age range, as well as additional occupational, dietary, medical, constitutional, and environmental exposures on SN neuron density and striatal dopamine levels. [unreadable] [unreadable]